Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically-induced endoplasmic reticulum stress - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Biochemical Journal Année : 2011

Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically-induced endoplasmic reticulum stress

Abdelali Agouni
  • Fonction : Auteur
Nimesh Mody
  • Fonction : Auteur
Carl Owen
  • Fonction : Auteur
Alicja Justyna Czopek
  • Fonction : Auteur
Derek Zimmer
  • Fonction : Auteur
Mohamed Bentires-Alj
  • Fonction : Auteur
Kendra K Bence
  • Fonction : Auteur

Résumé

Obesity is associated with induction of endoplasmic reticulum (ER)-stress response signalling and insulin resistance. Protein tyrosine phosphatase (PTP)-1B is a major regulator of adiposity and insulin sensitivity. The aim of this study was to investigate the role of liver-PTP1B in chronically- (high-fat diet) and pharmacologically-induced (tunicamycin, thapsigargin) ER-stress response signalling in vitro and in vivo. We assessed the effects of ER-stress response induction on hepatic PTP1B expression, and consequences of hepatic-PTP1B deficiency, in cells and mouse liver, on components of ER-stress response signalling. We found that PTP1B protein and mRNA expression levels were up-regulated in response to acute and/or chronic ER-stress, in vitro and in vivo. Silencing PTP1B in hepatic cell lines or mouse liver (L-PTP1B−/−) protected against induction of pharmacologically- and/or obesity-induced ER-stress. High-fat diet-induced increase in CHOP and BIP mRNA levels were partially inhibited, whereas ATF4, GADD34, GRP94, ERDJ4 mRNAs and ATF6 protein cleavage were completely suppressed in L-PTP1B−/− mice relative to control littermates. L-PTP1B−/− mice also had increased nuclear translocation of spliced XBP-1 via increased p85α binding. We demonstrate that the ER-stress response and liver-PTP1B expression are interlinked in obesity and pharmacologically-induced ER-stress and this may be one of the mechanisms behind improved insulin sensitivity and lower lipid accumulation in L-PTP1B−/− mice.

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Dates et versions

hal-00614617 , version 1 (13-08-2011)

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Abdelali Agouni, Nimesh Mody, Carl Owen, Alicja Justyna Czopek, Derek Zimmer, et al.. Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically-induced endoplasmic reticulum stress. Biochemical Journal, 2011, 438 (2), pp.369-378. ⟨10.1042/BJ20110373⟩. ⟨hal-00614617⟩

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